Injectable solution



United States Patent Ofiice 3,142,617 Patented July 28, 1964 3,142,617 INJECTABLE SOLUTION Leon Lachman, Summit, NJ, assignor to Ciba Corporation, a corporatian of New Jersey N Drawing. Filed July 15, 1959, Ser. No. 827,146 18 Claims. (Cl. 167-58) This invention relates to and has for its object the provision of injectable solutions of reserpine and related alkaloids, such as deserpidine and rescinnamine, as well as methods for their preparation.

The provision of injectable solutions of the Rauwolfia alkaloids has always posed a stability problem, especially where vial solutions are permitted to remain in that form for long periods before use. Thus, it has been found that such vial solutions of reserpine, are subject to both hydrolytic and oxidation-reduction degradation. Analytical results indicate that the degradation may yield products, such as 3,4,5-trimethoxy benzoic acid, tetrahydroreserpine (tetrahydrodeserpidine, tetrahydrorescinnamine, etc.) and isoreserpine (isodeserpidine, isorescinnamine, etc.). The 3,4,5-trimethoXy-benzoic acid normally precipitates and/or results in cloudy mixtures which are, of course, unsuitable for injection.

To overcome the above and related difficulties a formulation type has been developed which will inhibit hydrolysis at the ester linkage of the molecule and will also afford protection against the oxidation-reduction reaction which appears to take place generally in Ring C of the alkaloid molecule. To procure the desired effects according to the invention, it has been found essential to include in the injectable aqueous solution of reserpine (or related alkaloid) a combination of (1) an N-substituted amide (or mixture of such amides) and (2) a non-toxic acid having a pK of about 3 to about 5, more particularly of about 3.5 to about 4.5, especially about 4. Also desirably included in the solutions of the invention are non-toxic glycols, either in monomeric form or polymeric form. Such glycols include, inter alia, glycol; 1,2-propanediol; 1,2-butanediol, polyalkylene glycols having molecular weights between about 100 and about 20,000 including polyethylene glycols (i.e. Carbowaxes), such as Carbowax 300, Carbowax 1000, Carbowax 1500W, Carbowax 6000, etc. as well as the corresponding polypropylene glycols.

The N-substituted amides which constitute an essential ingredient of the compositions of the invention are preferably N-substituted or N,N-disubstituted amides of lower aliphatic acids, such as formic, acetic, propionic, butyric, sec-butyric, pentanoic, Q-methyl butyric, trimethylacetic, hexanoic, heptanoic, etc., also, chloroacetic acid, chlorpropionic acid, dichloroacetic acid, B-hydroxy propionic acid, etc. The substituent on the amide nitrogen is preferably an alkyl substituent, especially a lower alkyl substituent, such as methyl, ethyl, isopropyl, propyl, butyl, hexyl, etc., but may be any other aliphatic substituent, such as ,B-hydroxyethyl, B-chlorethyl, etc., or an aromatic substituent, such as phenyl, tolyl, chlorophenyl, etc or an aralkyl substituent, such as benzyl, phenethyl, chlorbenzyl, etc. Where polycarboxylic acids are used, there may be additional N-substituents on the amide nitrogen atoms. Thus, with dicarboxylic acids (particularly lower alkylene dicarboxylic acids), such as succinic acid, adipic acid, etc., one may have up to four substituents, such as lower alkyl substituents, on the amino nitrogen atoms. In addition, N-substituted and disubstituted ureas are included Within the purview of the invention, as are the analogous trisubstituted and tetrasubstituted ureas, etc. Thus, ureas, containing the same substituents as those mentioned above, may be employed in the invention. Specific examples of the substituted amides which may be used in the invention are N- or N,N-lower alkyl subabout 5 to about 30% stituted lower fatty acid amides, such as N-methylacetamide; N,N dimethylacetamide; N,N diethylpropionamide; N,N-dibutylpropionamide; N-amylpropionamide; N,N-dimethylbutyrarnide; N-ethylbutyramide; ureas substituted on at least one nitrogen atom by a hydrocarbon substituent (particularly a lower alkyl substituent), such as N,N-dimethylurea; N,N'-dimethylurea; N,N,N',N'- tetramethylurea; N,N-diethylurea; N,N-diethyl thiourea; N,N,N',N'-tetraethylurea; N,N-dipropylurea, etc. One may also use N-mono or poly-substituted (especially lower alkyl substituted) amides of lower alkylene dicarboxylic acids, such as N,N,N,N'-tetramethyl furnaramide; N,N- dimethyl fumaramide; N,N,N',N'-tetrarnethyl succinamide; N,N'-dimethyl succinamide; N,N'-diisopropyl succinamide; N,N,N',N'-tetramethyl glutaramide; N,N-diethyl adipamide, N-butyl adipamide, etc. In addition, one may use benzene mono and dicarboxylic acid amides wherein at least one nitrogen atom is substituted (especially those wherein the substituents on the nitrogen atom are lower alkyl, e.g. di-lower alkyl phthalamides or tetralower alkyl phthalamides). Examples of such com pounds are N,N,N,N-tetramethylphthalamide; N,N'- dimethylphthalamide; N-methyl phthalamide; N,N-diethyl phthalamide; N,N,N'N-tetramethyl isophthalamide; N,N,N,N'-tetrabutyl isophthalamide; N,N,N,N'-tetramethyl terephthalarnide; N,N-dipropyl terephthalamide; etc. In addition, one may advantageously utilize other amides, such as N-lower alkylated xanthines, e.g. 1,3,7-trimethylxanthine; 1,3,7-tributylxanthine, 1,3-dimethylxanthine; 3,7-dimethylxanthine; etc., or one may use N-substituted amide polymers, such as polyvinyl pyrrolidone, etc.

The non-toxic acids having a pK of about 3 to about 5 which are used in the inventive solutions are preferably alkane dicarboxylic acids, especially adipic but also in cluding other acids, such as malic, mandelic, tartaric,

lactic, acetic, hippuric, malonic, propionic, etc.

In the compositions of the invention the reserpine (or equivalent Rauwolfia alkaloids) may be present in an amount ranging from about 1 to about 10 mg. (preferably about 1 to 5, especially about 2.5 mg), per milliliter of solution, theN-substituted amide may be present in an amount ranging from about 5 to about 30% (preferably about 10 to 20, especially about 10%) of solution, the glycol may be present in an amount ranging from (preferably about 5 to 15, especially about 5%) of solution, and the acid having a pK of about 3 to about 5 may be present in an amount ranging from about 0.5 to about 2%, (preferably 0.5 to 1.5%, especially about 1.0%) adjusted so that no acid precipitates from the solution. [The term solution as used above refers, of course, to the final solution prepared for injection].

In addition to the essential components of the injectable solutions, including the water for injection, one may, of course, desirablyadd other ingredients. Thus, there may, for example, be included antioxidants, such as thiourea, sodium sulfite, sodium metabisulfite, ascorbic acid, cysteine hydrochloride, sodium formaldehyde sulfoxylate;

monothioglycerol, thiosorbitol, and chelating agents, such 35 Example 1 Materials and formula ml 1000 Reserpine g 2.500 Adipic acid g 10.000 N,N-dimethylacetamide ml 100 .000

Ethylenediamine tetraacetic acid monosodium salt g 0.100 Benzyl alcohol ml 10.000 Polyethylene glycol 300 ml 50.000 Ascorbic acid g 0.500 Sodium sulfite g 0.100 Water for injection, 1 q.s. ml 1000.000

Water for injection used is heated to a boil and then nitrogen gas passed through for 30 minutes.

Prcedure.-Dissolve the reserpine in the N,N-dimethylacetamide with stirring. Then add the adipic acid and dissolve. Add the polyethylene glycol 300 and benzyl alcohol and mix. Dissolve the sodium sulfite, ascorbic acid and ethylenediamine tetraacetic acid monosodium salt in 400 ml. of Water for injection. Add this solution to the reserpine solution and mix. Bring up to volume with water for injection and stir. Pass nitrogen gas through solution for 30 minutes. Filter solution through medium porosity filter. Fill into 2 ml. amber ampuls or m1. amber vials that have been previously flushed with nitrogen gas. Seal ampuls and stopper and cap vials. Sterilize in autoclave at 10 p.s.i., 115 C. for 30 minutes. pH 3.8.

Example 2 Materials and formula ml 1000 Reserpine g 2.500 N,N-dimethylacetan1ide ml 100.000 Polyethylene glycol 300 ml 100.000 Adipic acid g 10.000 Water for injection, q.s .rnl 1000.000

Pr0cedure.Dissolve the reserpine in the N,N-dimethyl acetamide. Add the adipic acid and stir until solution is affected; then add the polyethylene glycol 300 and stir. Bring up to volume with Water for injection. Pass nitrogen gas through finished solution for 30 minutes. Filter solution through a medium porosity filter. Fill into ampuls (or vials) that have been previously flushed with nitrogen gas. Sterilize at 115, 10 p.s.i. for 30 minutes.

Example 3 Using the identical procedure and composition as that used in Example 1, except that deserpidine (or rescinnamine) is substituted for the reserpine, one may prepare the analogous composition.

Example 4 Materials and formula ml 1000 Reserpine -g 2.500 N,N-dimethylacetamide ml 200.000 Adipic acid g 10.000 Water for injection, q.s ml 1000.000

Pr0cedure.Dissolve the reserpine in the N,N-dimethylacetamide. Then add the adipic acid and mix until a solution is obtained. Bring up to volume with water for injection. Pass nitrogen gas through finished solution for 30 minutes. Filter solution through a medium porosity filter. Fill into ampuls (or vials) that have been previously flushed with nitrogen gas. Sterilize at 115 10 p.s.i. for 30 minutes.

Example 5 Using the identical procedure and composition as that used in Example 4, except that deserpidine (or rescinnamine) is substituted for the reserpine, one may prepare the analogous composition.

Example 6 Materials and formula ml 1000 Reserpine g 2.500 N,N-dimethylacetamide rnl 100.000 Polyethylene glycol 300 ml 50.000 Benzyl alcohol rnl 10.000 Adipic acid g 10.000 Water for injection, q.s ml 1000.000

Procedure-Dissolve the reserpine in the N,N-dimethylacetamide. Add the adipic acid and mix until a solution is obtained. Then add the polyethylene glycol 300 and benzyl alcohol and stir, until a clear solution results. Bring up to volume with water for injection. Pass nitrogen gas through finished solution for 30 minutes. Filter solution through a medium porosity filter. Fill into ampuls (or vials) that have been previously flushed with nitrogen gas. Sterilize at 10 p.s.i. for 30 minutes.

solution is obtained. Then add the adipic and propionic acids and stir to attain uniformity. Dissolve the hydroquinone and ethylenediamine tetraacetic acid monosodium salt in about 200 ml. of water for injection and add to the reserpine solution and mix well. Bring up to volume with Water for injection. Pass nitrogen gas through finished solution for 30 minutes. Filter solution through a medium porosity filter. Fill into ampuls (or vials) that have been previously flushed with nitrogen gas. Sterilize at 115, 10 p.s.i. for 30 minutes.

Example 8 Materials and formula ml 1000 Reserpine g 2.500 N,N,N,N'-tetramethyl urea g 100.000 Polyethylene glycol 300 m 200.000 Benzyl alcohol ml.. 10.000 Adipic acid g 10.000 Water for injection, q.s ml 1000.000

Example 9 Materials and formula ml 1000 Reserpine ..g 2.500 Adipic acid g 10.000 N,N-dimethylacetamide ml 100.000 N,N,N,N'-tetramethyl urea g 50.000 Benzyl alcohol ml 10.000 Water for injection, q.s ml 1000.000

Pr0cedure.-Dissolve the reserpine in the N,N-dimethylacetamide. Add the adipic acid and mix until solution results. Then add the N,N,N',N'-tetramethyl urea and stir until all dissolved. Add the benzyl alcohol and mix. Bring up to volume with water for injection. Pass nitrogen gas through finished solution for 30 minutes. Filter solution through a medium porosity filter. Fill into ampuls (or vials) that have been previously flushed with nitrogen gas. Sterilize at 115, p.s.i. for 30 minutes.

This invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

1. An injectable aqueous solution consisting essentially of an efiective amount up to about 10 mg. of a member selected from the group consisting of reserpine, rescinnamine and deserpidine, about 5 to about 30 percent by weight of at least one N-substituted amide, each of said N-substituents being members selected from the group consisting of lower alkyl, hydroxy-lower alkyl, halolower alkyl, phenyl, lower alkyl-phenyl and halo-phenyl and about 0.5 to about 2.0 percent by weight of a soluble, non-toxic acid of pK about 3 to about 5, per millimeter of solution, said N-substituted amide being derived from those selected from the group consisting of urea, thiourea, a saturated lower aliphatic mono-carboxylic acid amide and a saturated lower aliphatic di-carboxylic acid amide.

2. A composition of claim 1, wherein an N-substituted amide is an amide containing two to four substituents on amino nitrogen atoms.

3. A composition of claim 1, wherein an N-substituted amide is an amide containing two substituents on amino nitrogen atoms.

4. A composition of claim 1, wherein an N-substituted amide is an amide containing three substituents on amino nitrogen atoms.

-5. A composition of claim 1, wherein the N-substituted amide is N,N-dimethylacetamide.

6. A composition of claim 5, wherein the soluble, nontoxic acid is adipic acid.

7. An injectable aqueous solution consisting essentially of an elfective amount up to about 10 mg. of reserpine, about 5 to about 30 percent by weight of at least one N-substituted amide, each of said N-substituents being members selected from the group consisting of lower alkyl, hydroxy-lower alkyl, halo-lower alkyl, phenyl, lower alkyl-phenyl and halo-phenyl and about 0.5 to about 2.0 percent by weight of a soluble, non-toxic acid of pK about 3 to about 5, per milliliter of solution, said N-substituted amide being derived from those selected from the group consisting of urea, thiourea, a saturated lower aliphatic mono-carboxylic acid amide and a saturated lower aliphatic di-carboxylic acid amide.

8. An injectable aqueous solution consisting essentially of about 1 to about 5 mg. of reserpine, about 10 to about 20 percent by weight of at least one N-substituted amide, each of said N-substituents being members selected from the group consisting of lower alkyl, hydroxylower alkyl, halo-lower alkyl, phenyl, lower alkyl-phenyl and halo-phenyl and about 0.5 to about 1.5 percent by weight of a soluble, non-toxic acid of pK about 3 to about 5, per milliliter of solution, said N-substituted amide being derived from those selected from the group consisting of urea, thiourea, a saturated lower aliphatic mono-carboxylic acid amide and a saturated lower aliphatic di-carboxylic acid amide.

9. An injectable aqueous solution consisting essentially of an elfective amount up to about 10 mg. of a member selected from the group consisting of reserpine, deserpidine and rescinnamine, about 5 to about 30 percent by weight of at least one N-substituted amide, each of said N-substituents being members selected from the group consisting of lower alkyl, hydroxy-lower alkyl, halolower alkyl, phenyl, lower alkyl-phenyl and halo-phenyl, about 0.5 to about 2.0 percent by weight of a soluble, non-toxic acid of pK about 3 to about 5 and about '5 to about 30 percent by weight of a poly-lower alkylene glycol having a molecular weight about 300 to about 20,000, per milliliter of solution, said N-substituted amide being derived from those selected from the group consisting of urea, thiourea, a saturated lower aliphatic mono-carboxylic acid amide and a saturated lower aliphatic di-carboxylic acid amide.

10. An injectable aqueous solution consisting essentially of an eifective amount up to about 10 mg. of reserpine, about 5 to about 30 percent by weight of at least one N-substituted amide, each of said N-sub'stituents being members selected from the group consisting of lower alkyl, hydroXy-lower alkyl, halo-lower alkyl, phenyl, lower alkyl-phenyl and halo-phenyl, about 0.5 to about 2.0 percent by weight of a soluble, non-toxic acid of pK about 3 to about 5 and about 5 to about 30 percent by weight of a poly-lower alkylene glycol having a molecular weight about 300 to about 20,000 per milliliter of solution, said N-substituted amide being derived from those selected from the group consisting of urea, thiourea, a saturated lower aliphatic mono-carboxylic acid amide and a saturated lower aliphatic di-carboxylic acid amide.

11. An injectable aqueous solution consisting essentially of about 1 to about 5 mg. of reserpine, about 10 to about 20 percent by weight of at least one N-substituted amide, each of said N-substituents being members selected from the group consisting of lower alkyl, hydroxy-lower alkyl, halo-lower alkyl, phenyl, lower alkyl-phenyl and halo-phenyl, about 0.5 to about 1.5 percent by weight of a soluble, non-toxic acid of pK about 3 to about 5 and about '5 to about 30 percent by weight of a polyethylene glycol having a molecular weight about 300 to about 20,000, per milliliter of solution, said N-substituted amide being derived from those selected from the group consisting of urea, thio urea, a saturated lower aliphatic mono-carboxylic acid amide and a saturated lower aliphatic di-carboxylic acid amide.

12. A composition of claim 11, wherein the N-substituted amide is N,N-dimethylacetamide.

13. A composition of claim 12, wherein the soluble, non-toxic acid is adipic acid.

14. An injectable aqueous solution consisting essentially of about 1 to about 10' mg. of reserpine, about 10 to about 20 percent by weight of at least one N-substituted amide, each of said N-substituents being members selected from the group consisting of lower alkyl, hydroxy-lower alkyl, halo-lower alkyl, phenyl, lower alkyl-phenyl and halo-phenyl, about 0.5 to about 1.5 percent by weight of a soluble, non-toxic acid of pK about 3.5 to about 4.5, per milliliter of solution, said N-substituted amide being derived from those selected from the group consisting of urea, thiourea, a saturated lower aliphatic mono-carboxylic acid amide and a saturated lower aliphatic di-carboxylic acid amide.

15. An injectable aqueous solution consisting essentially of about 1 to about 10 mg. of reserpine, about 10 to about 20 percent by weight of at least one N-substituted amide, each of said N-substituents being members selected from the group consisting of lower alkyl, hydroXy-lower alkyl, halo-lower alkyl, phenyl, lower alkyl-phenyl and halo-phenyl, about 0.5 to about 1.5 percent by weight of a soluble, non-toxic acid of pK about 3.5 to about 4.5 and about 15 percent by weight of a polyethylene glycol having a molecular weight about 300, said N-substituted amide being derived from those selected from the group consisting of urea, thiourea, a saturated lower aliphatic mono-carboxylic acid amide and a lower aliphatic di-carboxylic acid amide.

16. An injectable aqueous solution consisting essentially of about 2.5 mg. of reserpine, about 10 to about 20 percent by weight of N,N-dimethylacetamide and about 0.5 to about 1.5 percent by weight of a soluble, non-toxic acid of pK about 3.5 to about 4.5, per milliliter of solution.

17. An injectable aqueous solution consisting essentially of about 2.5 mg. of reserpine, about 10 percent 7 by weight N,N-dimethylacetamide and. about 1 percent by weight of adipic acid.

18. An injectable aqueous solution consisting essentially of about 2.5 mg. of reserpine, about 10 percent by weight N,N-dimethylacetamide, about 5 percent by weight polyethylene glycol having a molecular Weight about 300 and about 1 percent by weight of adipic acid, per milliliter of solution.

References Cited in the file of this patent UNITED STATES PATENTS 1,913,323 Aeschlimann June 6, 1933 8 Berendes et al. Aug. 8, 1933 Goth Jan. 14, 1936 Martin et a1 Aug. 17, 1948 Jensen et a1 Sept. 30, 1958 Martin et al Oct. 13, 1959 FOREIGN PATENTS Great Britain Feb. 28, 1930 .Great Britain May 17, 1938 

9. AN INJECTABLE AQUEOUS SOLUTION CONSISTING ESSENTIALLY OF AN EFFECTIVE AMOUNT UP TO ABOUT 10 MG. OF A MEMBER SELECTED FROM THE GROUP CONSISTING OF RESERPINE, DESERPIDINE AND RESCINNAMINE, ABOUT 5 TO ABOUT 30 PERCENT BY WEIGHT OF AT LEAST ONE N-SUBSTITUTED AMIDE, EACH OF SAID N-SUBSTITUENTS BEING MEMBERS SELECTED FROM THE GROUP CONSISTING OF LOWER ALKYL, HYDROXY-LOWER ALKYL, HALOLOWER ALKYL, PHENYL, LOWER ALKYL-PHENYL AND HALO-PHENYL, ABOUT 0.5 TO ABOUT 2.0 PERCENT BY WEIGHT OF A SOLUBLE, NON-TOXIC ACID OF PKA ABOUT 3 TO ABOUT 5 AND ABOUT 5 TO ABOUT 30 PERCENT BY WEIGHT OF A POLY-LOWER ALKYLENE GLYCOL HAVING A MOLECULAR WEIGHT ABOUT 300 TO ABOUT 20,000 PER MILLILITER OF SOLUTION, SAID N-SUBSTITUTED AMIDE BEING DERIVED FROM THOSE SELECTED FROM THE GROUP CONSISTING OF UREA, THIOUREA, A SATURATED LOWER ALIPHATIC MONO-CARBOXYLIC ACID AMIDE AND A SATURATED LOWER ALIPHATIC DI-CARBOXYLIC ACID AMIDE. 